The delivery of drugs and other agents to target cells or tissues for the treatment of cancer and other diseases has been the focus of considerable research for many years. Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., chemotherapeutic (anti-cancer), cytotoxic, enzyme inhibitor agents and antiviral or antimicrobial drugs) that can be administered. Although oral administration of drugs is considered to be a convenient and economical mode of administration, it shares the same concerns of non-specific toxicity to non-target cells once the drug has been absorbed into the systemic circulation. Further complications involve problems with oral bioavailability and residence of drug in the gut leading to additional exposure of gut to the drug and hence risk of gut toxicities.
Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. The benefits of such treatment include avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells. Intracellular targeting may be achieved by methods, compounds and formulations which allow accumulation or retention of agents, i.e. cytotoxic or cytostatic agents, inside cells. The use of antibody-drug conjugates for the local delivery of cytotoxic or cytostatic agents (e.g., drugs to kill or inhibit tumor cells in the treatment of cancer) can allow targeted delivery of the drug moiety to tumors, and intracellular accumulation therein. In contrast, systemic administration of unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated.
In antibody drug conjugates, the drug can be linked directly to the antibody (e.g., via a cysteine residue) or indirectly via a linker. Internalization of the target antibody following antigen binding carries the drug into the target cell. Once internalized, the drug can be released from the antibody by cleavage in the lysozme or by other cellular mechanism. To facilitate drug release, a cleavable site can be included in the linker. In some conjugates, a portion of a linker may remain attached to the drug after cleavage. To avoid this, a self-immolative spacer has been included in the linker. A self-immolative spacer is a bifunctional chemical moiety which is capable of covalently linking together two spaced chemical moieties into a normally stable tripartate molecule (e.g., an antibody-linker-drug conjugate). Following cleavage, the spacer spontaneously cleaves itself from the remainder of the molecule to release the other of said spaced chemical moieties. (See U.S. Pat. No. 6,214,345.) For example, one self-immolative spacer unit is p-aminobenzylcarbamoyl (PABC).
However, there is a need for an antibody drug conjugate which does not require a self-immolative spacer for efficient drug release from the antibody drug conjugate when linked through an enzymatically cleavable linker. These and other limitations and problems of the past are solved by the present invention. The recitation of any reference in this application is not an admission that the reference is prior art to this application.